ABSTRACT Late-life depression (LLD) is both a risk factor and a prodrome of Alzheimer?s disease. However, the inter- relationship of LLD and AD at the neural circuit level remains unclear. Understanding these neural circuit changes is important for developing treatment strategies for co-morbid depression in AD, and for preventing the development of AD in individuals with depression. Our ongoing NEMO LLD treatment study provides a unique opportunity to gather pilot data to explore these relationships. In the ongoing NEMO study, 100 individuals with LLD (with a range of cognitive impairment, excluding dementia) are recruited and randomized to treatment with a selective serotonin reuptake inhibitor (escitalopram) or a selective norepinephrine reuptake inhibitor (levomilnacipram). Functional MRI measures at rest, and with cognitive and emotional tasks, are done at 4 time points over the course of a 12-week trial, including a pair of scans 12 hours before and 12 hours after their first dose of medication. The circuit changes during this initial pharmacologic exposure measure ?target engagement? of the antidepressant. In this supplement, we propose adding AD Biomarkers (Amyloid imaging), an AD-sensitive fMRI task, and MR spectroscopy, to this ongoing study. The amyloid imaging will allow us to identify which participants have pre- clinical AD (estimated at > 25% in this non-demented elderly cohort), and thus characterize how AB may interfere with antidepressant target engagement (Aim 1). The addition of an AD-sensitive fMRI task and MRS will allow us to identify the role of excitotoxicity in the pathway from depression to dementia (Aim 2). In exploratory (Aim 3) we relate excitoxicity to AB load. Preliminary analyses using pre-clinical AD participants from a study of cognitive aging, suggest an important role for small vessel disease (WMH burden) in the excitotoxity pathway to AD. As WMH are a prominent feature in LLD, we hypothesize that these lesions help explain the pathway from LLD to AD (hypothesis 2.1). The new imaging measures proposed in this supplement will be collected on the 25 participants we anticipate recruiting over the 1-year period of this pilot grant. This will serve as preliminary data for planned studies that will be powered to confirm the specific neural circuit pathways that inter-relate Depression and AD.